Oxidative Damage as a Fundament of Systemic Toxicities Induced by Cisplatin-The Crucial Limitation or Potential Therapeutic Target?

Cisplatin, an inorganic complex of platinum, is a chemotherapeutic drug that has been used for 45 years. Despite the progress of pharmaceutical sciences and medicine and the successful application of other platinum complexes for the same purpose, cisplatin is still the therapy of choice in many cancers. Treatment for testicular, ovarian, head and neck, urothelial, cervical, esophageal, breast, and pulmonary malignancies is still unthinkable without the use of this drug. However, cisplatin is also known for many side effects, of which the most pronounced are nephrotoxicity leading to acute renal failure, neurotoxicity, and ototoxicity. Mechanistic studies have proven that one of the conditions that plays a major role in the development of cisplatin-induced toxicities is oxidative stress. Knowing the fact that numerous antioxidants can be used to reduce oxidative stress, thereby reducing tissue lesions, organ failure, and apoptosis at the cellular level, many studies have defined antioxidants as a priority for investigation as a cotreatment. To investigate the mechanism of antioxidant action in vivo, many animal models have been employed. In the last few years, studies have mostly used rodents and zebrafish models. In this article, some of the most recent investigations that used animal models are listed, and the advantages and disadvantages of such experimental studies are pointed out.

Simultaneous Administration of Hyperbaric Oxygen Therapy and Antioxidant Supplementation with Filipendula ulmaria Extract in the Treatment of Thermal Skin Injuries Alters Nociceptive Signalling and Wound Healing.

Background and Objectives: Thermal skin injuries are a prevalent cause of skin damage, potentially leading to severe morbidity and significant mortality. In this study, we intended to estimate the effects of HBO (hyperbaric oxygen treatment) and antioxidant supplementation with Filipendula ulmaria extract, individually and simultaneously, in the treatment of thermal skin injuries. Materials and Methods: As a thermal skin injury experimental model, we used two-month-old male Wistar albino rats. Thermal injuries were made with a solid aluminium bar at a constant temperature of 75 °C for 15 s. Hyperbaric oxygen treatment was performed in a specially constructed hyperbaric chamber for rats (HYB-C 300) for seven consecutive days (100% O2 at 2.5 ATA for 60 min). Antioxidant supplementation was performed with oral administration of Filipendula ulmaria extract dissolved in tap water to reach a final concentration of 100 mg/kg b.w. for seven consecutive days. Results: Simultaneous administration of hyperbaric oxygen therapy and antioxidant supplementation with Filipendula ulmaria extract significantly ameliorated the macroscopic and histopathological characteristics of the wound area and healing. Also, this therapeutic approach decreased the local expression of genes for proinflammatory mediators and increased the expression of the µ-opioid receptor and the MT1 and MT2 receptors in the wound area and spinal cord, with a consequent increase in reaction times in behavioural testing. Conclusions: In conclusion, the presented results of our study allow evidence for the advantages of the simultaneous employment of HBO and antioxidant supplementation in the treatment of thermal skin injuries, with special reference to the attenuation of painful sensations accompanied by this type of trauma.

Green Synthesis of Silver Nanoparticles Using Salvia verticillata and Filipendula ulmaria Extracts: Optimization of Synthesis, Biological Activities, and Catalytic Properties.

The study's objective was to obtain silver nanoparticles (SVAgNP and FUAgNP) using aqueous extracts of Salvia verticillata and Filipendula ulmaria. The optimal conditions for nanoparticle synthesis were determined and obtained; nanoparticles were then characterized using UV-Vis, Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), Dynamic Light Scattering (DLS), Scanning Electron Microscopy with Energy Dispersive Spectroscopy (SEM/EDS). SVAgNP and FUAgNP possessed a crystalline structure with 48.42% and 60.41% silver weight, respectively. The highest percentage of nanoparticles in the solution had a diameter between 40 and 70 nm. In DPPH˙ and ABTS˙+ methods, FUAgNP (IC50 15.82 and 59.85 µg/mL, respectively) demonstrated a higher antioxidant capacity than SVAgNP (IC50 73.47 and 79.49 µg/mL, respectively). Obtained nanoparticles also showed pronounced antibacterial activity (MIC ˂ 39.1 µg/mL for most of the tested bacteria), as well as high biocompatibility with the human fibroblast cell line MRC-5 and significant cytotoxicity on some cancer cell lines, especially on the human colon cancer HCT-116 cells (IC50 31.50 and 66.51 µg/mL for SVAgNP and FUAgNP, respectively). The nanoparticles demonstrated high catalytic effectiveness in degrading Congo red dye with NaBH4. The results showed a rapid and low-cost methodology for the synthesis of AgNPs using S. verticillata and F. ulmaria with promising biological potential.

An Overview of the Beneficial Role of Antioxidants in the Treatment of Nanoparticle-Induced Toxicities.

Nanoparticles (NPs) are used in many products and materials for humans such as electronics, in medicine for drug delivery, as biosensors, in biotechnology, and in agriculture, as ingredients in cosmetics and food supplements. Besides that, NPs may display potentially hazardous properties on human health and the environment as a consequence of their abundant use in life nowadays. Hence, there is increased interest of researchers to provide possible therapeutic agents or dietary supplements for the amelioration of NP-induced toxicity. This review summarizes the new findings in the research of the use of antioxidants as supplements for the prevention and alleviation of harmful effects caused by exposure of organisms to NPs. Also, mechanisms involved in the formation of NP-induced oxidative stress and protective mechanisms using different antioxidant substances have also been elaborated. This review also highlights the potential of naturally occurring antioxidants for the enhancement of the antioxidant defense systems in the prevention and mitigation of organism damage caused by NP-induced oxidative stress. Based on the presented results of the most recent studies, it may be concluded that the role of antioxidants in the prevention and treatment of nanoparticle-induced toxicity is unimpeachable. This is particularly important in terms of oxidative stress suppression.

The Antioxidant Supplementation with Filipendula ulmaria Extract Attenuates the Systemic Adverse Effects of Nanosized Calcium Phosphates in Rats.

The aim of this study was to investigate and compare the systemic toxicity of three nanosized calcium phosphates (CaPs): hydroxyapatite (HA), tricalcium phosphate (TCP), and amorphous calcium phosphate (ACP) in rats. Since those metallic compounds are widely used as bone replacement materials, including their use in oral surgery, CaPs were applied (per os) equimollary (17.8 mg/kg, 11 mg/kg, and 9.65 mg/kg b.w., respectively) for 30 days in order to mimic the previously described release rate from dental composites. Also, we employed antioxidant supplementation with Filipendula ulmaria (FU) extract. All the applied CaPs significantly increased serum calcium, triglycerides, LDL, and LDH, while serum levels of testosterone and LH declined, with no alterations in the liver enzymes. The evaluation of oxidative stress markers (in the liver, kidney, and testicle) showed an increase in TBARS values, while SOD and CAT activities and GSH levels were significantly reduced. The relative gene expression of Bax and Bcl-2 was shifted to proapoptotic action, accompanied by intense characteristic histological changes in architecture in all investigated organs. The toxic effects were most prominent in groups treated by ACP. FU administration attenuated the majority of nanosized CaP-induced adverse effects, thus recommending this therapeutic approach to minimize nano-CaP systemic toxicities.

Application potential of biogenically synthesized silver nanoparticles using Lythrum salicaria L. extracts as pharmaceuticals and catalysts for organic pollutant degradation.

This study was designed to evaluate the optimal conditions for the eco-friendly synthesis of silver nanoparticles (AgNPs) using Lythrum salicaria L. (Lythraceae) aqueous extracts and their potential application and safe use. AgNPs synthesized using L. salicaria aerial parts (LSA-AgNPs) and root extract (LSR-AgNPs) were characterized by UV-Vis spectrophotometry, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM/EDS), and X-ray powder diffraction (XRPD). Dynamic light scattering (DLS) was used for the determination of the size distribution profiles of the obtained nanoparticles. Both L. salicaria extracts showed high phenolic content, while the flavone C-glucosides orientin, vitexin, and isovitexin were detected in extracts using HPLC. The synthesized AgNPs displayed growth inhibition of the tested bacteria and fungi in concentrations between 0.156 and 1.25 mg mL-1. The studied nanoparticles also showed antioxidant potential and gained selectivity at different concentrations on different cancer cell lines. Concentrations of LSA-AgNPs were found to be 20.5 and 12 µg mL-1 towards A431 and SVT2, respectively, while LSR-AgNPs were effective only against A431 cancer cells (62 µg mL-1). The hemolytic activity of LSA-AgNPs in concentrations up to 150 µg mL-1 was not observed, while LSR-AgNPs in the highest applied concentration hemolyzed 2.8% of erythrocytes. The degradation possibility of Congo red and 4-nitrophenol using LSA-AgNPs and LSR-AgNPs as catalysts was also proven. The results indicate that L. salicaria may be used for the eco-friendly synthesis of AgNPs with possible applications as antimicrobial and selective cytotoxic agents towards cancer cell lines, as well as in catalytic degradation of pollutants.

N-Acetylcysteine Protects against the Anxiogenic Response to Cisplatin in Rats.

Since cisplatin therapy is usually accompanied with numerous toxicities, including neurotoxicity, that involve tissue oxidative damage, the aim of this study was to evaluate the possible protective effect of N-acetylcysteine (NAC) on the anxiogenic response to cisplatin (CIS). Thirty-two male Wistar albino rats divided into four groups (control, cisplatin, NAC, and CIS + NAC). All treatments were delivered intraperitoneally. On day one, the control and cisplatin groups received saline while the NAC and CIS + NAC groups were administered with NAC (500 mg/kg). On the fifth day, the control group received saline while the CIS group was treated with cisplatin (7.5 mg/kg), the NAC group again received NAC (500 mg/kg), and the CIS + NAC group was simultaneously treated with cisplatin and NAC (7.5 and 500 mg/kg, respectively). Behavioral testing, performed on the tenth day in the open field (OF) and elevated plus maze (EPM) tests, revealed the anxiogenic effect of cisplatin that was significantly attenuated by NAC. The hippocampal sections evaluation showed increased oxidative stress (increased lipid peroxidation and decline in antioxidant enzymes activity) and proapoptotic action (predominantly by diminished antiapoptotic gene expression) following a single dose of cisplatin. NAC supplementation along with cisplatin administration reversed the prooxidative and proapoptotic effects of cisplatin. In conclusion, the results obtained in this study confirmed that antioxidant supplementation with NAC may attenuate the cisplatin-induced anxiety. The mechanism of anxiolytic effect achieved by NAC may include the decline in oxidative damage that down regulates increased apoptosis and reverses the anxiogenic action of cisplatin.